Type 1 Diabetes Mellitus (T1D) is an autoimmune disorder in which pancreatic beta ([unreadable]) cells, which produce insulin, are mistaken as foreign by one's own immune system and gradually destroyed. As a result of the body's own destruction of the [unreadable] cells, insulin production decreases and insulin levels become insufficient to control glucose levels, resulting in T1D. Although the etiology of T1D is only partially understood, it is felt that viruses play an important role in its pathogenesis. Viral infection of [unreadable] cells is suggested to initiate disease in a variety of ways including direct [unreadable] cell damage, release of [unreadable] cell antigens stimulating the autoimmune destruction, or toxicity to the [unreadable] cells by a variety of antiviral responses. Recent studies have implicated Toll-Like Receptors (TLR) in the pathogenesis of T1D. Specifically, TLR are molecules located on immune cells which recognize foreign antigens and initiate the protective immune response. TLR3 have recently been shown to be abnormally expressed directly on the pancreatic [unreadable] cells of patients with new onset T1D. In addition, the Coxsackie B virus (CBV), which has been associated with the development of T1D in humans, can activate TLR3 signaling and accelerate the development of T1D in non-obese diabetic (NOD) mice. The development of novel TLR signaling inhibitors which block this aberrant immune response causing T1D would offer a potentially new therapeutic paradigm to intervene and prevent [unreadable] cell destruction prior to onset of T1D or salvage [unreadable]-cells at initial onset. Phenylmethimazole (C10) is a compound which has been shown to prevent pathologic TLR overexpression and signaling in other TLR-mediated autoimmune diseases such as Hashimoto's Thyroiditis and Systemic Lupus Erythematosis. Thus C10 may have potential efficacy in the prevention or treatment of T1D through inhibition of TLR3 signaling and cytokine production and prevent [unreadable] cell apoptosis (programmed cell death) and/or immune destruction of [unreadable] cells. Preliminary studies show that C10 can prevent T1D in a NOD mouse model of virus-induced T1D. We hypothesize (1) that T-lymphocyte-mediated autoimmune destruction of insulin producing [unreadable] cells, and induction of [unreadable] cell death is the result of viral-activation of TLR3 signaling in the [unreadable] cell and (2) that C10's effective anti- inflammatory actions, mediated through the inhibition of TLR3 signaling, may prevent the onset of T1D and/or rescue [unreadable] cells and preserve insulin secretory function in new-onset T1D. Thus, the specific aim of this proposal is to evaluate the contribution(s) of TLR3 signaling to CBV-4-induced acceleration of T1D in NOD mice and the mechanism by which C10 attenuates CBV-4 acceleration of T1D in the NOD mouse by investigating its effects on (i) [unreadable] cell TLR3 signaling, (ii) insulitis (inflammation of the pancreas which precedes T1D), (iii) [unreadable] cell number, and (iv) specific immune cell populations within the pancreas. These studies will (1) provide a better understanding of the involvement of TLR3 signaling in the pathogenesis of T1D, and (2) evaluate the efficacy of a potentially novel new drug for the treatment/prevention of T1D. PUBLIC HEALTH RELEVANCE: Toll-Like Receptors (TLRs) have recently been implicated in environmental (viral) induction of type 1 diabetes (T1D). We investigate the possibility that viral induction of T1D is mediated through TLR3, and evaluate the efficacy of a novel TLR signaling inhibitor to prevent/delay the onset of T1D. Pursuit of these data may provide a better understanding of the involvement of TLR3 signaling in the pathogenesis of T1D, and evaluate the efficacy of a potentially novel new drug for the treatment/prevention of T1D.